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Substrate specificity of rat Na + /taurocholate cotransporting polypeptide
Author(s) -
Sheng Zhonghua,
Alnouti Yazen,
Hagenbuch Bruno
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.747.5
Subject(s) - troglitazone , chemistry , pharmacology , rosiglitazone , organic cation transport proteins , pravastatin , transporter , ic50 , biochemistry , receptor , biology , cholesterol , peroxisome proliferator activated receptor , in vitro , gene
Human Na + /taurocholate cotransporting polypeptide (NTCP) has recently been proposed to be a multispecific transporter that mediates uptake of xenobiotics including some statins in addition to its prototypical substrate (bile acids). In rat basolateral plasma membrane vesicles Na + ‐dependent taurocholate uptake was competitively inhibited by several glitazones, suggesting that these drugs could be substrates of rat Ntcp. Therefore we used CHO cells that stably express rat Ntcp to screen for drugs and other xenobiotics that inhibit sodium dependent taurocholate uptake and therefore might be substrates of Ntcp. We tested selected inhibitors as substrates using LC‐MS/MS analysis. We confirmed that troglitazone and rosiglitazone are strong inhibitors of rat Ntcp (IC50 = 13 μM for troglitazone, 8 μM for rosiglitazone). Furthermore, we determined that several additional drugs including losartan, ritonavir, saquinavir, fluvastatin, ketoconazole, diclofenac and carbenoxolone inhibited Ntcp mediated taurocholate transport in a concentration dependent pattern. The so far tested troglitazone, rosiglitazone, ritonavir, saquinavir and pravastatin however are not substrates for rat Ntcp although pravastatin is transported by human NTCP. In conclusion, rat Ntcp is inhibited by numerous drugs but its substrate specificity seems to be more restricted than the substrate specificity of human NTCP.